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Purpose: NRAS plays a pivotal role in progression of various kinds of somatic malignancies; however, the correlation between NRAS and lung adenocarcinoma is less known. We aim to analyze the prognostic value of NRAS expression in lung adenocarcinoma, and explore the relationship between NRAS and tumor immune microenvironment. Methods: We obtained the transcriptome pofiles and clinical data of LUAD from The Cancer Genome Atlas database and three Genome Expression Omnibus datasets. Specimens from 325 patients with completely resected lung adenocarcinoma were collected for immunohistochemical assays of NRAS, PD-L1, PD-1 and TIM-3. Then we performed gene set enrichment analysis to investigate cancer-related and immune-related signaling pathways. TIMER algorithms were performed to evaluate tumor immune infiltrating cells and immune-related biomarkers.Results: Compared with adjacent non-tumor tissue, NRAS expression was significantly upregulated in LUAD tissue. NRAS expression was significantly correlated with more advanced stage and positive lymph nodes. Kaplan-Meier curves and Cox analysis suggested that high NRAS expression led to a poor prognosis, and could be an independent prognostic factor in LUAD patients. Besides, NRAS expression was positively correlated with CD8+ T cells, macrophages, and neutrophils, and negatively correlated with B cells and CD4+ T cells. The expression level of NRAS was positively correlated with PD-L1, PD-1, and TIM-3 both at RNA and protein level. Conclusions: To conclude, we found NRAS a novel prognostic biomarker in LUAD. Besides, the expression level of NRAS may influence the prognosis of LUAD via various kinds of cancer-related pathways and remodeling TIM.

No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients. Significance: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Postoperative early relapse of early-stage lung adenocarcinoma is implicated in poor prognosis. The purpose of our study was to develop an integrated mRNA and non-coding RNA (ncRNA) signature to identify patients at high risk of early relapse in stage I–II lung adenocarcinoma who underwent complete resection. Early-stage lung adenocarcinoma data from Gene Expression Omnibus database were divided into training set and testing set. Propensity score matching analysis was performed between patients in early relapse group and long-term nonrelapse group from training set. Transcriptome analysis, random survival forest and LASSO Cox regression model were used to build an early relapse-related multigene signature. The robustness of the signature was evaluated in testing set and RNA-Seq dataset from The Cancer Genome Atlas (TCGA). The chemotherapy sensitivity, tumor microenvironment and mutation landscape related to the signature were explored using bioinformatics analysis. Twelve mRNAs and one ncRNA were selected. The multigene signature achieved a strong power for early relapse prediction in training set (HR 3.19, 95% CI 2.16–4.72, P

This is the first investigation that identified seasonal variation, possible sources and health risk of 16 PAHs in street dust sampled park area (PA), educational area (EA), commercial area (CA), residential area (RA), and traffic area (TA) of Chengdu, one of the new first-tier cities in China. The total PAHs (∑16PAHs) concentrations of averaging over two seasons varied from 2.15 to 10.6 mg/kg with a median value of 4.61 mg/kg and in winter (5.48 ± 1.52 mg/kg) were significantly higher than that in summer (4.04 ± 0.91 mg/kg). The highest ∑16PAHs concentration was found in TA (median 6.74 mg/kg). Statistical analysis results indicated that mixture sources of petroleum combustion and combustion of biomass and coal seem to be the primary source of the PAHs in street dust. Carcinogenic risk by incremental lifetime cancer risk (ILCR) model for PAHs in street dust indicates an acceptable potential cancer risk for residents. The same sequences of cancer risk to be observed for both children and adults among different functional areas: TA > CA > EA > RA > PA. The results provided advice for habitants in Chengdu to encourage outdoor activities in parks and residential areas and minimize traffic areas and commercial areas.

The low abundance of circulating tumour DNA (ctDNA) in plasma samples makes the analysis of ctDNA biomarkers for the detection or monitoring of early-stage cancers challenging. Here we show that deep methylation sequencing aided by a machine-learning classifier of methylation patterns enables the detection of tumour-derived signals at dilution factors as low as 1 in 10,000. For a total of 308 patients with surgery-resectable lung cancer and 261 age- and sex-matched non-cancer control individuals recruited from two hospitals, the assay detected 52-81% of the patients at disease stages IA to III with a specificity of 96% (95% confidence interval (CI) 93-98%). In a subgroup of 115 individuals, the assay identified, at 100% specificity (95% CI 91-100%), nearly twice as many patients with cancer as those identified by ultradeep mutation sequencing analysis. The low amounts of ctDNA permitted by machine-learning-aided deep methylation sequencing could provide advantages in cancer screening and the assessment of treatment efficacy.

Satisfactory tumor material is often hard to obtain for molecular analysis in extranodal natural killer (NK)/T-cell lymphoma (NKTCL) at present. However, the accuracy and utility of circulating cell-free DNA (cfDNA) genotyping have not been adequately assessed in NKTCL. We therefore performed targeted next-generation sequencing on tumor tissues and a series of longitudinal plasma samples prospectively collected from a cohort of high-risk NKTCL patients. Concordance of genotyping results of paired baseline tumor and cfDNA and the predictive value of dynamic cfDNA monitoring were evaluated. At baseline, 59 somatic variants in 31 genes were identified in tumor and/or plasma cfDNA among 19 out of 24 high-risk NKTCL patients (79.2%). Plasma cfDNA had a sensitivity of 72.4% for detection of somatic variants identified in tumor biopsies before treatment. Plasma cfDNA also allowed the identification of mutations that were undetectable in tumor biopsies. These results were also verified in a validation cohort of an additional 23 high-risk NKTCL patients. Furthermore, longitudinal analysis showed that patients with rapid clearance of NKTCL-related mutations from plasma had higher complete remission rates (80.0% vs 0%; P = .004) and more favorable survival (1-year progression-free survival [PFS] rate, 79.0% vs 20.0%; P = .002) compared with those with persisting or emerging mutations in plasma. In addition, low cfDNA concentration before treatment was associated with favorable survival outcome for patients with NKTCL (1-year PFS, 90.0% vs 36.4%; P = .012). In conclusion, cfDNA mirrors tumor biopsy for detection of genetic alterations in NKTCL and noninvasive dynamic plasma cfDNA monitoring might be a promising approach for tracking response and survival outcome for patients with NKTCL.

Lung squamous cell carcinoma (LUSC) represents a major subtype of non-small cell lung cancer with limited treatment options. Previous studies have elucidated the complex genetic landscape of LUSC and revealed multiple altered genes and pathways. However, in stark contrast to lung adenocarcinoma, few targetable driver mutations have been established so far and targeted therapies for LUSC remain unsuccessful. Immunotherapy has revolutionized LUSC treatment and is currently approved as the new standard of care. To gain a better understanding of the LUSC biology, improved modeling systems are urgently needed. Preclinical models, particularly those mimicking human disease with an intact tumor immune microenvironment, are an invaluable tool to study cancer development and evaluate new therapeutic targets. Here, we discuss recent advances in LUSC preclinical models, with a focus on genetically engineered mouse models (GEMMs) and organoids, in the context of evolving precision medicine and immunotherapy.

Recent studies have indicated that CD47, interacting with SIRP-α, conveys “don’t eat me” signal in evasion of tumor cells and serves as a potential target for cancer immunotherapy. The purpose of this study was to investigate the clinical correlation of CD47 and uncover prognostic implications of CD47 and CD68 in non-small cell lung cancer (NSCLC). The specimens from 384 patients with completely resected NSCLC were collected for immunohistochemical assays of CD47 and CD68. Cox multivariate proportion hazard analyses were conducted to confirm the independent prognostic value of CD47 and CD68. TCGA database and GSE37745 were used to identify the association between CD47 and immune cells. In 186 pairs of lung cancer and adjacent tissues, the RNA of CD47 was overexpressed in lung cancer tissues (P

Objective: Lung adenocarcinoma (LADC) is classified into five main histological subtypes with distinct clinicopathologic characteristics: lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary-predominant adenocarcinoma (MPA) and solid-predominant adenocarcinoma (SPA). However, the mutational profiles of predominant histological subtypes have not been well defined. In this study, we aimed to reveal the genomic landscape of 5 main histological subtypes. Patients and Methods: We performed next-generation sequencing (NGS) in a cohort of 86 stage I invasive adenocarcinoma (IAC) patients, using a customized panel including 168 cancer-associated genes. Results: Our analysis identified a total of 302 genomic alterations. Five subtypes showed different mutation profiles with LPA, APA, PPA, MPA and SPA had an average mutation rate of 1.95 (range: 0-5), 2.56 (range: 1-6), 3.5 (range: 1-7), 3.75 (range: 1-8) and 6.05 (range: 2-12), respectively (p=4.17e-06). Driver mutations occurred in 96.55% (83/86) of all patients. EGFR (73.3%), KRAS (9.3%), ALK (4.7%) and MET (4.7%) are the most commonly mutated lung cancer driver genes, TP53 is the top mutated tumor suppressor gene. SPA patients harbored more driver mutations and higher frequency of TP53 than LPA patients. Interestingly, LRP1B mutations, which has been reported to be associated with high tumor mutation burden and better response to immunotherapy, were only detected from 5 SPA patients (p=0.001). No patients from other four cohorts harbored LRP1B mutations. Conclusions: We revealed distinctive mutation landscape of the 5 major histological subtypes of LADC, evident by distinctive average mutation rate with SPA and LPA having the highest and lowest average mutation rate, respectively. SPA patients showed higher mutation rate of LRP1B and higher rates for PD-L1 positivity, indicating that SPA patients may have better response to immunotherapy.

Stage I lung adenocarcinoma usually has a good prognosis after surgery. However, some patients do suffer disease recurrence during follow-up. Here, we report the prognostic value of evolutionary action score of TP53, which calculates the functional prediction of TP53, in patients with stage I lung adenocarcinoma. From January 2011 to August 2013, 83 patients with a complete follow-up history (36 with a disease recurrence and 47 without recurrence during follow-up) who were pathologically confirmed stage I lung adenocarcinoma were included. Whole-exome sequencing were performed on those paired tumor-normal specimens. Evolutionary action score of TP53 (EAp53) was calculated and patients were divided into groups according to their TP53 mutational status. Tumor mutational burden and survival analyses were performed to assess the prognostic value of EAp53. TP53 mutation was identified in 31 patients (37.3%). Of them, 11 were high-risk point mutations, 9 were low-risk point mutations, and 11 were truncating mutations. The high-risk group showed a poorer recurrence-free survival compared with the low-risk group (P = 0.046) and the wild-type group (P = 0.007). In multivariable analysis, the high-risk/truncating group showed a poorer recurrence-free survival (P = 0.007) and overall survival (P = 0.009) compared with the low-risk/wild-type group. Moreover, tumor mutational burden was higher in the high-risk/truncating group (P0.001). EAp53 is of prognostic value in patients with stage I lung adenocarcinoma. The mutational type of TP53 should be paid attention to when predicting the prognosis of patients with stage I lung adenocarcinoma.

Chronic liver disease represents stepwise destruction of the liver parenchyma after chronic liver injury, which is often difficult to be diagnosed accurately. Thus, the development of specific biomarkers of chronic liver disease is important. Metabolomics is a powerful tool for biomarker exploration, which enables the exploration of disease pathogenesis or drug action mechanisms at the global metabolic level. The metabolomics workflow generally includes collection, preparation, and analysis of samples, and data processing and bioinformatics. A metabolomics study can simultaneously detect the dysfunctions in the glucose, lipid, amino-acid, and nucleotide metabolisms. Hence, it facilitates the obtaining of a better understanding of the pathogenesis of chronic liver disease and its diagnosis. Many effective drugs could reverse the change of comprehensive biochemical phenotypes induced by chronic liver disease. They can even potentially restore the normal metabolic signatures of patients. Increasingly more researchers have begun to apply metabolomics technologies to diagnose chronic liver disease and investigate the mechanism of action of effective drugs or the variations in drug responses. We are convinced that deepening the understanding of the metabolic alterations could extend their use as powerful biomarkers, promoting the more effective clinical diagnosis and treatment of chronic liver disease in the future.

Background Most studies on MET exon 14 (MET-ex14) alteration, defined as an oncogenic driver, have been carried out among Caucasians; similar studies among Chinese people are limited. Methods We retrospectively analyzed the genomic profiles of 11,306 Chinese patients with various stages of lung cancer to investigate the prevalence of MET-ex14. Survival outcomes were analyzed in evaluable patients who received front-line crizotinib (n = 44) or chemotherapy (n = 14). Results MET-ex14 alterations were identified in 125 patients, a frequency of 1.1 %, which is much lower than that in Caucasians (∼2.7 %). We found that MET-ex14 alterations were more likely to be detected in older patients (median age 69.0 years, p Conclusions Our study demonstrated a prevalence of 1.1 % for MET-ex14 alterations among the Chinese population. Our study also contributes to a better understanding of molecular factors that are associated with clinical outcomes of patients with MET exon 14 alterations.

Background To validate the reliability and validity of the Chinese version of the THINC-it tool in adults with major depressive disorder (MDD). Methods Subjects aged 18 to 65 years (n=117) with MDD were evaluated and compared to age- and sex-matched healthy controls (n=124). Subjects completed the THINC-it, four criteria-related objective cognitive subtests, and the paper version of Perceived Deficits Questionnaire for Depression-5-item (PDQ-5-D). Results There were significant differences in Spotter [Mean difference (MD) Standard errors (SE)=-0.40 (0.17), P=0.018; 95% Confidence intervals (CI) (-0.73 to -0.07)]; Codebreaker [MD (SE)=-0.39 (0.14), P=0.006; 95% CI(-0.67 to -0.11)]; and the overall performance of four objective tests (including variants of IDN, OBK, DSST, and TMT-B) [MD (SE)=-0.30 (0.12), P=0.013; 95% CI (-0.53 to -0.06]) between the two groups. In the HC group, PDQ-5-D retest reliability was good (ICC = 0.841), and the test-retest reliability of the objective cognitive test was relatively low (ICC ranging from 0.123 to 0.545). In the MDD group: Cronbach's α of PDQ-5-D=0.704; all the THINC-it subtests had good concurrent validity (r ranging from 0.343 to 0.835, all P Limitation The test-retest sample size was relatively small, the educational level and IQ of the control and MDD groups were not completely matched. Conclusion The Chinese version of the THINC-it tool exhibits good reliability and validity in adults with MDD. There is a need to incorporate cognitive assessment of adults with MDD broadly. The THINC-it tool is the first tool validated to assess cognition of MDD in a Chinese population.

Current NCCN guidelines do not recommend the use of adjuvant chemotherapy for stage IA lung adenocarcinoma patients with R0 surgery. However, 25% to 40% of patients with stage IA disease experience recurrence. Stratifying patients according to the recurrence risk may tailor adjuvant therapy and surveillance imaging for those with a higher risk. However, prognostic markers are often identified by comparing high-risk and low-risk cases which might introduce bias due to the widespread interpatient heterogeneity. Here, we developed a scoring system quantifying the degree of field cancerization in adjacent normal tissues and revealed its association with disease-free survival (DFS). Methods: We recruited a cohort of 44 patients with resected stage IA lung adenocarcinoma who did not receive adjuvant therapy. Both tumor and adjacent normal tissues were obtained from each patient and subjected to capture-based targeted genomic and epigenomic profiling. A novel methylome-based scoring system namely malignancy density ratio (MD ratio) was developed based on 39 patients by comparing tumor and corresponding adjacent normal tissues of each patient. A MD score was then obtained by Wald statistics. The correlations of MD ratio, MD score, and genomic features with clinical outcome were investigated. Results: Patients with a high-risk MD ratio showed a significantly shorter postsurgical DFS compared with those with a low-risk MD ratio (HR=4.47, P=0.01). The MD ratio was not associated with T stage (P=1), tumor cell fraction (P=0.748) nor inflammatory status (p=0.548). Patients with a high-risk MD score also demonstrated an inferior DFS (HR=4.69, P=0.039). In addition, multivariate analysis revealed EGFR 19 del (HR=5.39, P=0.012) and MD score (HR= 7.90, P=0.01) were independent prognostic markers. Conclusion: The novel methylome-based scoring system, developed by comparing the signatures between tumor and corresponding adjacent normal tissues of individual patients, largely minimizes the bias of interpatient heterogeneity and reveals a robust prognostic value in patients with resected lung adenocarcinoma.

PURPOSE To compare refractive error measured by hand-held wavefront aberrometers with postcycloplegic autorefraction (AR) and cycloplegic refraction (CR). METHODS The medical records of patients who received refractive measurements using the wavefront aberrometer, postcycloplegic AR, and CR between January 2014 and January 2016 were retrospectively analyzed. The mean differences, 95% confidence intervals, and limits of agreement (LOA) were calculated for the refractive vector components (M, J₀, and J45 ). RESULTS Fifty-one patients (9.0 ± 5.5 years, male 41.2%) were enrolled in this study, and only the right eye of each was included. Refractive errors ranged from -9.25 to +7.25 diopters (D) for spherical equivalent (median, 0.75 D). The M component was not significantly different among the three methods (p = 0.080). However, the J₀ vector component was significantly different (p < 0.001). After post hoc analysis, the wavefront aberrometer obtained more positive values for J₀ compared to the other methods. The J45 component was not significantly different among the three methods (p = 0.143). The mean difference between the wavefront aberrometer and postcycloplegic AR was -0.115 D (LOA, -1.578 to 1.348 D) for M, 0.239 D (LOA, -0.371 to 0.850 D) for J₀, and -0.015 D (LOA, -0.768 to 0.738 D) for J45 . The mean difference between the wavefront aberrometer and CR was -0.220 D (LOA, -1.790 to 1.350 D) for M, 0.300 D (LOA, -0.526 to 1.127 D) for J₀, and -0.079 D (-0.662 to 0.504 D) for J45 . CONCLUSIONS The wavefront aberrometer showed good agreement with postcycloplegic AR and CR in spherical equivalents, but tended to produce slightly myopic results. The wavefront aberrometer also overestimated with-the-rule astigmatism. Therefore, we recommend that the device be used for estimations of refractive error, which may be useful for patients who have postural difficulties, live in undeveloped countries, or are bedridden.

One of the most common sites of extra-thoracic distant metastasis of nonsmall-cell lung cancer is the brain. Our study was performed to discover genes associated with postoperative brain metastasis in operable lung adenocarcinoma (LUAD). RNA seq was performed in specimens of primary LUAD from seven patients with brain metastases and 45 patients without recurrence. Immunohistochemical (IHC) assays of the differentially expressed genes were conducted in 272 surgical-resected LUAD specimens. LASSO Cox regression was used to filter genes related to brain metastasis and construct brain metastasis score (BMS). GSE31210 and GSE50081 were used as validation datasets of the model. Gene Set Enrichment Analysis was performed in patients stratified by risk of brain metastasis in the TCGA database. Through the initial screening, eight genes (CDK1, KPNA2, KIF11, ASPM, CEP55, HJURP, TYMS and TTK) were selected for IHC analyses. The BMS based on protein expression levels of five genes (TYMS, CDK1, HJURP, CEP55 and KIF11) was highly predictive of brain metastasis in our cohort (12-month AUC: 0.791, 36-month AUC: 0.766, 60-month AUC: 0.812). The validation of BMS on overall survival of GSE31210 and GSE50081 also showed excellent predictive value (GSE31210, 12-month AUC: 0.682, 36-month AUC: 0.713, 60-month AUC: 0.762; GSE50081, 12-month AUC: 0.706, 36-month AUC: 0.700, 60-month AUC: 0.724). Further analyses showed high BMS was associated with pathways of cell cycle and DNA repair. A five-gene predictive model exhibits potential clinical utility for the prediction of postoperative brain metastasis and the individual management of patients with LUAD after radical resection.

To understand the molecular mechanism of tumorigenesis of pulmonary lymphoepithelioma-like carcinoma and explore potential therapeutic strategies, we investigated the genomic profiles and PD-L1 expression of 29 Chinese pulmonary lymphoepithelioma-like carcinoma patients at various stages. We performed capture-based targeted sequencing on tissue samples collected from 27 patients with sufficient samples using a panel consisting of 520 cancer-related genes, spanning 1.64 Mb of the human genome. We identified 184 somatic mutations in 109 genes from 26 patients. One patient had no mutations detected by this panel. Copy number variations were detected in 52% (14/27) of the patients, with a majority having advanced-stage disease (10/14). Except for the detection of ERBB2 amplification and KRAS mutation in two patients, no other classic lung cancer driver mutations were detected. Interestingly, 78% (21/27) of the patients had mutations in epigenetic regulators. Of the 184 mutations identified, 51 occurred in 29 epigenetics-related genes. Furthermore, we performed PD-L1 immunohistochemistry staining using the Dako 22C3 assay and demonstrated that 69% (20/29) of the cohort had positive PD-L1 expression, of which three patients received and benefited from a PD-1 inhibitor. In conclusion, we elucidated a distinct genomic landscape associated with pulmonary lymphoepithelioma-like carcinoma with no classic lung cancer driver mutation but an enrichment of mutations in epigenetic regulators. The detection of high PD-L1 expression and lack of any canonical druggable driver mutations raises the potential of checkpoint immunotherapy for pulmonary lymphoepithelioma-like carcinoma.

Yiping He,1,2,* Xiaoji Ma,1,2,* Ke Chen,2,3,* Fangqi Liu,1,2 Sanjun Cai,1,2 Han Han-Zhang,4 Ting Hou,4 Jianxing Xiang,4 Junjie Peng1,2 1Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People’s Republic of China; 3Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai 200032, People’s Republic of China; 4Burning Rock Biotech, Guangzhou, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Junjie PengDepartment of Colorectal Surgery, Fudan University Shanghai Cancer Center, 270 Dong’An Road, Shanghai 200032, People’s Republic of ChinaTel +86 21 64175590Email pengjj67@hotmail.comBackground: The surgical resection of colorectal cancer with liver metastases (CLM) has proven to be the most important modality for long-term survival, while effective biomarkers for outcome prediction or postoperative surveillance are still lacking. Currently, circulating biomarkers obtained from a liquid biopsy are widely used to assess the treatment response, disease recurrence and progression. In this study, we analyzed the value of the liquid biopsy, which includes circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA), in patients with CLM.Methods: Capture-based targeted deep sequencing was performed on matched pre-surgery, post-surgery and liver metastatic tissues of 20 CRC patients who underwent the resection of liver metastases between May and September 2017 using a panel consisting of 41 genes. Mutation landscapes obtained from pre-surgery plasma samples and metastatic tissue samples were compared.Results: Collectively, we identified 47 mutations from 17 pre-surgery plasma samples (85%), and the remaining 3 patients had no mutation detected from the panel. We revealed a high by-variant concordance rate of 82.14% between pre-surgery plasma samples and liver metastatic tissue samples. We further analyzed the correlation between ctDNA, cfDNA, CEA and tumor burden and revealed a positive correlation between ctDNA and tumor burden (R=0.69, p=0.002). As of the date for data cutoff, 8/20 patients experienced relapse. Our study also demonstrated that pre-surgery ctDNA (p< 0.001), cfDNA (p=0.001) and CEA (p=0.012) levels had predictive value for relapse. Patients with low pre-surgery ctDNA (p< 0.001), cfDNA (p=0.001) or CEA (p=0.012) levels were more likely to experience prolonged progression-free survival.Conclusion: Our data demonstrate that the genomic profile obtained from ctDNA is comparable with the genomic profile obtained from metastatic liver tumors. Furthermore, our study also show that pre-surgery ctDNA levels are positively correlated with tumor burden. In addition, pre-surgery ctDNA, cfDNA and CEA levels have predictive value for relapse.Keywords: colorectal liver metastases, CLM, circulating tumor DNA, ctDNA, tumor burden, prognosis

HER2-positive breast cancer is a biologically and clinically heterogeneous disease. Based on the expression of hormone receptors (HR), breast tumors can be further categorized into HR positive and HR negative. Here, we elucidated the comprehensive somatic mutation profile of HR+ and HR− HER2-positive breast tumors to understand their molecular heterogeneity. In this study, 64 HR+/HER2+ and 43 HR-/HER2+ stage I-III breast cancer patients were included. Capture-based targeted sequencing was performed using a panel consisting of 520 cancer-related genes, spanning 1.64 megabases of the human genome. A total of 1119 mutations were detected among the 107 HER2-positive patients. TP53, CDK12 and PIK3CA were the most frequently mutated, with mutation rates of 76, 61 and 49, respectively. HR+/HER2+ tumors had more gene amplification, splice site and frameshift mutations and a smaller number of missense, nonsense and insertion-deletion mutations than HR-/HER2+ tumors. In KEGG analysis, HR+/HER2+ tumors had more mutations in genes involved in homologous recombination (P = 0.004), TGF-beta (P = 0.007) and WNT (P = 0.002) signaling pathways than HR-/HER2+ tumors. Moreover, comparative analysis of our cohort with datasets from The Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium revealed the distinct somatic mutation profile of Chinese HER2-positive breast cancer patients. Our study revealed the heterogeneity of somatic mutations between HR+/HER2+ and HR-/HER2+ in Chinese breast cancer patients. The distinct mutation profile and related pathways are potentially relevant in the development of optimal treatment strategies for this subset of patients.

Background: Herein, we validate the psychometric properties of the Chinese version of the THINC-integrated tool (THINC-it) as a screening tool for cognitive deficits in patients with major depressive disorder. The primary aim of this study is to determine whether cognitive deficits as detected by the THINC-it tool in adults with major depressive disorder (MDD) are associated with workplace productivity and/or psychosocial function.Methods: Subjects aged 18–65 (n = 91) with MDD were evaluated and compared to age-, sex- and education- matched healthy controls (n = 95). Symptoms of cognitive dysfunction, workplace productivity, and psychosocial function were measured using the THINC-it tool, Hamilton Depression Scale (HAMD), Sheehan Disability Scale (SDS), The Work Productivity and Activity Impairment questionnaire- Specific Health Problem (WPAI-SHP).Results: There were significant differences in THINC-it scores (p < 0.01), the average of HAMD total score (p < 0.01) and all aspects of SDS (p < 0.01) between two groups. There were significant differences in the four aspects of WPAI between the two groups in the employed status (p r ranging from 0.255 to 0.386, p r ranging

Objective: To observe the characteristics and evaluate the efficacy and safety of the chronic total rhegmatogenous retinal detachment (RRD) treatment by the 23-gauge pars plana vitrectomy (PPV) in young adults and to analyze the related factors.Methods: A retrospective chart review was performed for the young adults who underwent the 23-gauge PPV for the chronic total RRD at the Tianjin Medical University General Hospital from 2011 to 2018. A total of 54 eyes of 48 patients were included in this study. The preoperative vision ranged from 2.00 to 1.00. The mean duration of RRD was 9 ± 0.6 months with a range from 4 to 18 months. The proliferative vitreoretinopathy (PVR) grade D1 and grade D2 was diagnosed in 48 eyes and 6 eyes, respectively. About 37 eyes were filled with C3F8 and 17 eyes were filled with silicone oil tamponade. The follow-up ranged from 9 to 78 months with a mean of 23 ± 2.2 months.Results: The postoperative visual acuity increased in all the eyes at the final observation. The retinal attachment was achieved in 49 eyes (90.7%) in the primary PPV. Five eyes (9.3%) with the failed retinal attachment finally achieved the attachment after the second procedure. The postoperative complications mainly included temporary intraocular pressure (IOP) elevation, hyphema, and retinal redetachment.Conclusion: Chronic total RRD can be treated via the 23-gauge PPV with a great anatomical and visual prognosis in the young adult. The successful treatment of the chronic total RRD in young adults is mainly associated with the complete dissection of the severe vitreoretinopathy, especially for the epiretinal membrane at the retinal breaks and degenerations and the subretinal proliferation during surgery.

Purpose To characterize vitreous microparticles (MPs) in patients with traumatic proliferative vitreoretinopathy (PVR) and investigate their role in PVR pathogenesis. Methods Vitreous MPs were characterized in patients with traumatic PVR, patients with rhegmatogenous retinal detachment (RRD) complicated with PVR, and control subjects by flow cytometry. The presence of M2 macrophages in epiretinal membranes was measured by immunostaining. Vitreous cytokines were quantified by ELISA assay. For in vitro studies, MPs isolated from THP-1 cell differentiated M1 and M2 macrophages, termed M1-MPs and M2-MPs, were used. The effects and mechanisms of M1-MPs and M2-MPs on RPE cell proliferation, migration, and epithelial to mesenchymal transition were analyzed. Results Vitreous MPs derived from photoreceptors, microglia, and macrophages were significantly increased in patients with traumatic PVR in comparison with control and patients with RRD (PVR), whereas no significance was identified between the two control groups. M2 macrophages were present in epiretinal membranes, and their signature cytokines were markedly elevated in the vitreous of patients with traumatic PVR. Moreover, MPs from M2 macrophages were increased in the vitreous of patients with traumatic PVR. In vitro analyses showed that M2-MPs promoted the proliferation and migration of RPE cells via activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. However, M2-MPs did not induce the expression of fibrotic proteins, including fibronectin, α-smooth muscle actin, and N-cadherin in RPE cells. Conclusions This study demonstrated increased MP shedding in the vitreous of patients with traumatic PVR; specifically, MPs derived from M2 polarized macrophages may contribute to PVR progression by stimulating RPE cell proliferation and migration.

Background IBI362 (LY3305677) is a novel weekly-dose glucagon-like peptide-1 and glucagon receptor dual agonist being developed for the treatment of obesity and type 2 diabetes. The aim of this randomised, placebo-controlled, multiple ascending dose phase 1b study was to evaluate the safety, tolerability, pharmacokinetics and efficacy of IBI362 in Chinese adults with overweight or obesity. Methods This study enrolled adults with overweight (body mass index [BMI]≥24 kg/m2) accompanied by hyperphagia and/or at least one comorbidity or obesity (BMI≥28 kg/m2) from six study centres in China. Eligible participants were randomised 2:1 to receive once-weekly subcutaneous injection of IBI362 or placebo in each of the three ascending dose cohorts for 12 weeks with additional 8 weeks of safety follow-up. The dose-escalation regimens were: 3.0 mg cohort (1.0 mg weeks 1–4; 2.0 mg weeks 5–8; 3.0 mg weeks 9–12); 4.5 mg cohort (1.5 mg weeks 1–4; 3.0 mg weeks 5–8; 4.5 mg weeks 9–12); 6.0 mg cohort (2.0 mg weeks 1–4; 4.0 mg weeks 5–8; 6.0 mg weeks 9–12). The participants, investigators and study site personnel involved in treating and assessing participants within each cohort were masked to treatment allocation. The primary endpoints were safety and tolerability of IBI362. This study is registered with ClinicalTrials.gov, number NCT04440345. Findings Between June 15th, 2020 and January 15th, 2021, 12 participants were enrolled and randomised in each cohort. Throughout the study, no participant discontinued the treatment due to safety reason and no serious adverse event was reported. Gastrointestinal adverse events and decreased appetite were the most common adverse events and mostly mild in severity. Three participants receiving IBI362 reported mild and asymptomatic cardiac disorders revealed by electrocardiogram. Estimated percent changes in mean body weight from baseline to week 12 were −4.81% (95%CI −6.61 to −3.02), −6.40% (−8.23 to −4.58) and −6.05% (−7.91 to −4.18) for participants receiving IBI362 in the 3.0 mg, 4.5 mg and 6.0 mg cohort, respectively, compared with 0.60% (−0.86 to 2.07) for those receiving placebo. Interpretation IBI362 was well tolerated and showed a body weight-lowering effect in Chinese adults with overweight or obesity. Funding Innovent Biologics.

Background Distinction in the mutational profile between the common histological types, lung adenocarcinoma (LUAD) and squamous cell lung carcinoma (LUSC) has been well‐established. However, comprehensive mutation profiles of the predominant histological subtypes within LUAD and LUSC remains elusive. Methods We analyzed the mutational profile of 318 Chinese NSCLC patients of adenocarcinoma and squamous cell carcinoma predominant subtypes from seven hospitals using capture‐based ultra‐deep sequencing of 68 lung cancer‐related genes. Results Of the 318 NSCLC patients, 215 were diagnosed with LUAD and 103 with LUSC. Adenocarcinoma in situ and acinar adenocarcinoma were the most predominant subtypes of LUAD. On the other hand, keratinizing squamous cell carcinoma was the most predominant subtype of LUSC. Among the LUAD subtypes, EGFR sensitizing mutations were most prevalent in the invasive lepidic subtype. More than half of the patients with preinvasive adenocarcinoma in situ, minimally invasive, acinar, micropapillary and papillary subtypes were also EGFR‐mutants. Patients with colloidal, invasive mucinous, and fetal subtypes had the least number of EGFR mutations. Moreover, KRAS mutations were prevalent in patients with invasive mucinous, colloid, enteric and solid subtypes. A total of 90% of the LUSC patients harbor mutations in TP53, wherein all patients except five with nonkeratinizing were TP53 mutants. PIK3CA amplifications were most prevalent in keratinizing, followed by basaloid and nonkeratinizing subtypes. Conclusion These data suggest that the mutational profiles among the predominant histological subtypes were very distinct, which provided a reliable tool to improve treatment decisions.

Recent studies have indicated that the presence of ground-glass opacity (GGO) components is associated with favorable survival. The purpose of this study was to reveal the prognostic value of GGO components and differences in prognostic factors for part-solid and solid lesions in invasive stage I NSCLC.The cases of 2010 patients with completely resected invasive pathological stage I NSCLC were reviewed according to the eighth edition of the TNM classification. Patients were categorized into the pure-GGO, part-solid, and solid groups based on consolidation-to-tumor ratio. Cox multivariate proportional hazard analyses were conducted to identify independent prognostic factors in each group.Of the 2010 patients, 146 (7.3%) were in the pure-GGO group, 732 (36.4%) were in the part-solid group, and 1132 (56.3%) were in the solid group. Cox multivariate analyses revealed that GGO absence was a strong independent risk factor for worse recurrence-free survival (p0.001). For the pure-GGO group, there was no recurrence in spite of the invasive stage. For the part-solid group, visceral pleural invasion could not predict recurrence-free survival in general (p = 0.514) or in each tumor size group (for tumors size ≤1 cm, p = 0.664; for tumors size1 to 2 cm, p = 0.456; for tumors size2 to 3 cm, p = 0.900; and for tumors size3 to 4 cm, p = 0.397). For the solid group, adenocarcinoma subtype was not a prognostic factor for recurrence-free survival in general (p = 0.162) or in each tumor size group (for tumors size ≤ 2 cm, p = 0.092; for tumors size2 to 3 cm, p = 0.330; and for tumors size3 to 4 cm, p = 0.885).The presence of GGO components was a strong predictor in patients with invasive pathological stage I NSCLC. Risk factors were distinct in the part-solid and solid groups. There was no prognostic value of visceral pleural invasion in the part-solid group. Adenocarcinoma subtype did not have prognostic value in the solid group.

To describe characteristics of recurrent intermittent exotropia after bilateral lateral rectus (BLR) recession, and identify factors associated with poor outcome after unilateral medial rectus (MR) resection for recurrent intermittent exotropia. We retrospectively reviewed 124 patients who have undergone unilateral MR resection for recurrent intermittent exotropia after BLR recession. Patients were followed for at least 2 years after MR resection. Clinical characteristics and risk factors associated with poor outcome after unilateral MR resection were evaluated. Successful outcome was defined as distant deviation within the range of 4 prism diopters (PD) esotropia and 10 PD exotropia at last visit after MR resection. Among 124 patients, 50 patients (41.1%) were male, and the mean age at the time of MR resection was 9.5 ± 3.1 years. The average follow-up period after MR resection was 43.8 ± 23.7 months. Forty-seven patients (37.9%) were classified to have poor outcome at last visit, and 29 patients (23.4%) underwent third operation. None of the patients was overcorrected after MR resection. Multiple logistic regression analyses showed that distant deviation at post-operative 3 months and male gender were associated with poor outcome (OR 1.49; 95% CI 1.27–1.73; P

Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment., The genomic and immune landscape of pre-invasive lung adenocarcinoma is poorly understood. Here, the authors perform exome and transcriptome sequencing on precursor legions and invasive lung adenocarcinomas, identifying recurrently mutated genes in pre/minimally invasive cases, and arm level alteration events linked to immune infiltration.

Objective KRAS mutation plays a critical role in the initiation and development of non‐small cell lung cancer (NSCLC). KRAS‐mutant patients exhibit diverse response to chemotherapy. KRAS co‐mutation subtypes and their prognosis value in advanced Chinese NSCLC patients remain largely elusive. Methods A total of 1126 Chinese advanced NSCLC patients from Xiangya hospital were screened by capture‐based ultra‐deep sequencing for KRAS mutation between January 2015 and December 2016. Survival analyses were performed using Kaplan‐Meier analysis. Results Among the patients screened, 84 cases were detected with KRAS mutation (7.5%). All of them were non‐squamous NSCLC and received pemetrexed plus platinum as the first‐line treatment. The most frequent KRAS co‐mutation genes were TP53 (29%), TP53/LKB1 (19%), and LKB1 (14%). Our data revealed that patients with KRAS co‐mutation had poorer prognosis in comparison with those harboring single KRAS mutation. Furthermore, patients with KPL (KRAS mutated with TP53 and LKB1) subtype, which was a novel subtype, had the shortest progression‐free survival (PFS) in all types of KRAS co‐mutation patients (P T type had significantly longer survival than those in KRASG>C type or KRASG>A type. Conclusion Our study revealed that concurrent genomic alterations can further stratify KRAS‐mutant lung adenocarcinoma patients into various subgroups with distinctive therapeutic responses and differential survival outcomes. The KPL is a novel and less responsive subtype among KRAS‐mutated NSCLC, and further investigation of effective treatment for this subtype is warranted., Our study revealed that concurrent genomic alterations can further stratify KRAS‐mutant lung adenocarcinoma patients into various subgroups with distinctive therapeutic responses and differential survival outcomes. The KPL is a novel and less responsive subtype among KRAS‐mutated NSCLC, and further investigation of effective treatment for this subtype is warranted.

Afatinib has improved the prognosis of epidermal growth factor receptor-positive advanced non-small cell lung cancer and has been explored in the treatment of human epidermal growth factor receptor 2 (HER2)-amplified breast cancer. However, its clinical efficacy in HER2-amplified endometrial cancer has not been reported. Herein, we present the clinical benefit of afatinib in a case of stage IIIC endometrioid adenocarcinoma refractory to multiple lines of chemotherapy and eventually developed pulmonary, abdominal and pelvic metastasis. Upon referral to our clinic, capture-based targeted sequencing was performed on both blood and tumor samples and revealed HER2 amplification. The patient was administered with afatinib and achieved partial response (PR) after two months of treatment, reflected by a significant reduction in pulmonary lesions and serum levels of tumor markers including carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9, 125, 15-3 and cytokeratin 19 fragment antigen 21-1 (CY211). The patient passed away after 3 months of afatinib treatment due to suspected complications of severe intestinal obstruction. Our report demonstrates the efficacy of afatinib in a heavily pre-treated HER2-amplified endometrial cancer patient with multi-organ metastasis. This case also highlights the need to include comprehensive mutational profiling in the standard management of endometrial cancer patients for treatment guidance.

Background The classification of large cell neuroendocrine carcinoma (LCNEC) has generated considerable debate and has been revised since its recognition as a separate entity. Although it shares clinical features with small cell lung carcinoma (SCLC) and was classified with SCLC in the 2015 World Health Organization classification system, numerous studies have revealed inferior treatment outcomes of LCNEC when it was treated as SCLC. Because the incidence of LCNEC is rare, its mutational landscape has not been comprehensively interrogated. Methods We performed capture-based ultra-deep targeted sequencing on tumor samples of LCNEC, large cell carcinoma (LCC), and SCLC to elucidate its biological relationship with these subtypes and to identify potentially targetable molecular alterations. Results Our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC. A majority (60%) of LCNEC patients harbored copy number variations (CNVs). Interestingly, there were no common CNVs shared among the three subtypes: NFкBIA amplification was shared between LCNEC and LCC, while AKT2 amplification was shared between LCNEC and SCLC. Furthermore, genetic alterations in the PI3K/AKT/mTOR pathway were enriched in all three subtypes. Conclusion Despite the histological and/or morphological similarities among LCNEC, LCC, and SCLC, our data revealed a molecular signature, consisting of RUNX1, ERBB4, BRCA1, and EPHA3, that is distinctively mutated in LCNEC, which has the potential to be used as a panel of biomarkers to distinguish LCNEC from a molecular perspective. Furthermore, the molecular distinction among the three subtypes can also be reflected from CNV events.

Background Evidence shows that low serum vitamin D concentrations account for an increased risk of obesity by inducing vitamin D receptor (VDR) hypofunction. Although the correlation between single nucleotide polymorphisms (SNPs) of VDR gene and obesity-related anthropometric measures (such as body mass index [BMI] and waist circumference[WC]) has already been tested, there are only few studies on the association between direct measures of body fat percentage (BFP) and triceps skinfold thickness and the SNPs of VDR. The aim of the present study was to evaluate the effect of VDR gene polymorphism on multiple obesity indexes in Han Chinese, including BMI, WC, BFP and triceps skinfold thickness. Methods In this cross-sectional study, five hundred and seventeen healthy Chinese adults were enrolled in the trial. Four loci in VDR gene (rs2228570 [FokI], rs2189480, rs2239179 and rs7975232[ApaI]) were genotyped by TaqMan probe assays. Obesity indexes including BMI, WC, BFP and triceps skinfold thickness were used to evaluate the relationship to the VDR SNPs. Multiple logistic regression, linear regression and general multifactor dimensionality reduction (GMDR) were performed to analyze the correlation of VDR gene and obesity indexes. Results None of the VDR SNPs were associated with BMI and WC, the C allele of FokI and the T allele of ApaI were associated with an increase in BFP (β = 0.069,P = 0.007; β = 0.087, P = 0.022 respectively); the G allele of rs2239179 and the T allele of ApaI were associated with an increase in triceps skin fold thickness (β = 0.074, P = 0.001; β = 0.122, P

OBJECTIVE To evaluate the association of a healthy lifestyle, involving seven low-risk factors mentioned in diabetes management guidelines (no current smoking, moderate alcohol consumption, regular physical activity, healthy diet, less sedentary behavior, adequate sleep duration, and appropriate social connection), with all-cause and cause-specific mortality among individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS This study included 13,366 participants with baseline type 2 diabetes from the UK Biobank free of cardiovascular disease (CVD) and cancer. Lifestyle information was collected through a baseline questionnaire. RESULTS During a median follow-up of 11.7 years, 1,561 deaths were documented, with 625 from cancer, 370 from CVD, 115 from respiratory disease, 81 from digestive disease, and 74 from neurodegenerative disease. In multivariate-adjusted model, each lifestyle factor was significantly associated with all-cause mortality, and hazard ratios associated with the lifestyle score (scoring 6–7 vs. 0–2 unless specified) were 0.42 (95% CI 0.34, 0.52) for all-cause mortality, 0.57 (0.41, 0.80) for cancer mortality, 0.35 (0.22, 0.56) for CVD mortality, 0.26 (0.10, 0.63) for respiratory mortality, and 0.28 (0.14, 0.53) for digestive mortality (scoring 5–7 vs. 0–2). In the population-attributable risk analysis, 29.4% (95% CI 17.9%, 40.9%) of deaths were attributable to a poor lifestyle (scoring 0–5). The association between a healthy lifestyle and all-cause mortality was consistent, irrespective of factors reflecting diabetes severity (diabetes duration, glycemic control, diabetes-related microvascular disease, and diabetes medication). CONCLUSIONS A healthy lifestyle was associated with a lower risk of all-cause mortality and mortality due to CVD, cancer, respiratory disease, and digestive disease among individuals with type 2 diabetes.

Colorectal cancer (CRC) is the second most common cause of cancer death in the world, and metastatic CRC is a major cause of cancer death. Gallotannin (GT), a polyphenolic compound, has shown various biological effects such as anti-oxidant, anti-inflammatory, antimicrobial, and antitumor effects. However, the effects of GT on metastatic CRC cells are not completely understood. This study aimed to investigate the anti-metastatic effect of GT and the underlying mechanisms on metastatic CRC cells. Oral administration of GT suppressed the lung metastasis of metastatic CRC cells in the experimental mouse model. GT decreased the viability of metastatic CRC cell lines, including CT26, HCT116, and SW620, by inducing apoptosis through the activation of extrinsic and intrinsic pathways, cell cycle arrest through inactivation of CDK2/cyclin A complex, and autophagic cell death through up-regulation of LC3B and p62 levels. GT regulated PI3K/AKT/mTOR and AMPK signaling pathways, which are critical for the development and maintenance of cancer. Additionally, non-cytotoxic concentrations of GT can suppress migration and invasion of CRC cells by inhibiting the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 and epithelial-mesenchymal transition by downregulating the expression of mesenchymal markers including snail, twist, and vimentin. In conclusion, GT prevented colorectal lung metastasis by reducing survival and inhibiting the metastatic phenotypes of CRC cells.

Inactivating mutations in LKB1/STK11 are present in roughly 20% of nonsmall cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy. Unexpectedly, we found that LKB1 deficiency correlated with elevated tumor mutational burden (TMB) in NSCLCs from nonsmokers and genetically engineered mouse models, despite the frequent association between high-TMB and anti-PD-1 treatment efficacy. However, LKB1 deficiency also suppressed antigen processing and presentation, which are associated with compromised immunoproteasome activity and increased autophagic flux. Immunoproteasome activity and antigen presentation were restored by inhibiting autophagy through targeting the ATG1/ULK1 pathway. Accordingly, ULK1 inhibition synergized with PD-1 antibody blockade, provoking effector T-cell expansion and tumor regression in Lkb1-mutant tumor models. This study reveals an interplay between the immunoproteasome and autophagic catabolism in antigen processing and immune recognition, and proposes the therapeutic potential of dual ULK1 and PD-1 inhibition in LKB1-mutant NSCLC as a strategy to enhance antigen presentation and to promote antitumor immunity. Wong and colleagues show that LKB1-deficient lung tumors are sensitive to autophagy inhibition, which can restore impaired antigen presentation and antitumor immune responses, and propose dual targeting of ULK1 and PD-1 for these tumors.

ObjectivesVarious genomic alterations and genomic signatures, including ERBB2 amplification, mutations in PIK3CA, AKT1, and ESR1, and tumor mutational burden (TMB), have become important biomarkers for treatment selection in breast cancer (BC). This study aimed to investigate the mutational features of Chinese early-stage BC patients.MethodsTumors and matched blood samples collected from 589 Chinese patients with early-stage BC were sequenced using a commercial gene panel consisting of 520 cancer-related genes to analyze all types of genomic alterations and estimate the TMB status.ResultsA total of 18 genes were found to be more frequently mutated (PPPPP10mutations/Mb were found in 5.7% of our cohort. Although the TMB was similar for various molecular subtypes between our cohort and the BC cohort of The Cancer Genome Atlas (TCGA) study, the TMB were statistically different for HR+/HER-, HR+/HER2+, and triple-negative subtypes between our cohort and African Americans in the TCGA study. As compared to the TCGA BC cohort, our cohort had a much earlier median age of diagnosis (48 vs. 58 years, PPPTP53, ERBB2, and PIK3CA were distinct for patients who were younger (≤35 years), had triple-negative or invasive lobular BC in our cohort than in the TCGA cohort.ConclusionsThis study revealed distinct mutational features of various molecular subtypes of early-stage BC among Chinese patients. Moreover, we provide new insights into the differences in early-stage BC between the East and West.

BACKGROUND: Immune function is a key component affecting tumor progression in patients with cancer. The purpose of this study was to identify the prognostic value of systemic immune-inflammation index (SII) in patients with non-small cell lung cancer (NSCLC) and the differences of its prognostic value in patients with distinct characteristics. METHODS: Patients with completely resected NSCLC were reviewed according to the eighth TNM classification of lung cancer. Patients were further categorized into the low- and high-SII groups. Cox proportional hazard analyses were performed to identify the independent prognostic factors. RESULTS: A total of 3984 patients with NSCLC were enrolled in this study. Kaplan-Meier analyses demonstrated that high SII was associated with worse recurrence-free survival (RFS) (P

Purpose: To investigate the incidence, characteristics, and risk factors of sports-related eye injuries among athletes in Tianjin, China.Methods: A cross-sectional study was carried out from March 2018 to October 2018. In this study, the athletes from Tianjin University of Sports, Tianjin Vocational College of Sports, and Tianjin provincial sports teams were selected for general investigation. In total, 1,673 athletes were invited and 1,413 participated in the study (response rate of 84.5%).Results: In total, 1,413 athletes were enrolled; 151 had suffered from sports-related eye injuries, with an incidence of 10.7% (95% CI: 9.1–12.0%). Handball (38.5%) was the sport with the highest incidence of eye injuries, followed by water polo (36.4%) and diving (26.7%). Overall, 42.4% of the athletes were injured by ball and 22.5% of injuries came from teammates. The eye injuries usually occurred during training (64.2%) and competitions (14.6%). Adnexa wound (51.7%) was the most common type of injury. About 11.9% of the athletes with eye injuries had the impaired vision; 66.7% failed to see doctors on time. The athletes OR] =1.60, 95% CI: 1.06–2.40). The athletes with lower family income (OR = 3.91, 95% CI: 2.24–6.82). Training >4 h a day increased the risk of eye injuries (OR = 2.21, 95% CI: 1.42–3.43).Conclusion: The incidence of sports-related eye injuries among athletes was 10.7% in Tianjin, China. Handball, water polo, and diving were the most common activities of injury. Age, family income, and training time were the risk factors for sports-related eye injuries.

Variants in the TUBB3 gene, one of the tubulin-encoding genes, are known to cause congenital fibrosis of the extraocular muscles type 3 and/or malformations of cortical development. Herein, we report a case of a 6-month-old infant with c.967A>G:p.(M323V) variant in the TUBB3 gene, who had only infantile nystagmus without other ophthalmological abnormalities. Subsequent brain magnetic resonance imaging (MRI) revealed cortical dysplasia. Neurological examinations did not reveal gross or fine motor functions, which are inconsistent with the clinical characteristics of patients with the M323V syndrome reported so far. A protein modeling showed that the M323V mutation in the TUBB3 gene interferes with αβ heterodimer formation with the TUBA1A gene. This report emphasizes the importance of considering TUBB3 and TUBA1A tubulinopathy in infantile nystagmus. A brain MRI should also be considered for these patients, although in the absence of other neurologic signs or symptoms.

Long noncoding RNA (LncRNA) H19 has been proven to be involved in many kinds of cancers including glioma, and a previous study has shown an autophagy regulation of H19. The mammalian target of rapamycin (mTOR) signaling pathway plays a key role in autophagy and Unc-51 like autophagy activating kinase 1 (ULK1) is also thought to be involved in autophagy signaling. In our study, we investigated the role of mTOR/ULK1 autophagy signaling in the H19-mediated promotion of glioma proliferation. Human glioma cells U87 and U251 and normal human astrocytes HA1800 were used in the study. First, the expression of H19 was determined in U87, U251, and HA1800 cells. Then, the cell proliferation and migration of glioma cells were detected, while the protein levels of main molecules of the mTOR/ULK1 pathway and autophagy-related proteins were also examined. Rapamycin, an inhibitor of mTOR, was used to further study the role of H19 in autophagy. We observed that overexpressed H19 promoted the proliferation and migration in glioma cells. The autophagy of U87 cells was suppressed when H19 was overexpressed and enhanced when H19 was silenced. H19 overexpression inhibited mTOR phosphorylation and promoted ULK1 phosphorylation. H19 promoted proliferation, migration, and autophagy by regulating mTOR signaling. In conclusion, we validate that H19 contributes to the proliferation and autophagy of glioma cells through the mTOR/ULK1 pathway.

BACKGROUND: HER2 transmembrane domain (TMD) mutation has been reported as a rare driver mutation associated with advanced stage disease and a poor prognosis in patients with lung adenocarcinoma (LUAD). We aimed to comprehensively profile the genetic landscape and treatment response information of HER2 TMD-mutant LUAD. METHODS: An in-house database of 7,812 LUAD patients was screened for mutation prevalence. A multi-center cohort of 16 HER2 V659E-mutant patients and an external cohort of 38 HER2-mutant patients from cBioPortal with overall survival (OS) data were analyzed. Eight patients from the in-house cohort were included in the real-world study of treatment response. Molecular docking simulation and binding affinity prediction were performed. RESULTS: In Chinese LUAD, the prevalence of HER2 TMD mutation was 0.18% (14/7,812), and 0.14% (11/7,812) for the HER2 V659E mutation. The most recurrent co-alteration was TP53 mutation (n=4, 25%) and HER2 amplification (n=2, 12.5%). TMD-mutant patients were diagnosed at more advance stages (P

BACKGROUND: Mutations in POLE /POLD1 proofreading domain can cause deficiencies in DNA repair, conferring ultramutated cancer phenotypes. Preliminary clinical studies have revealed an association between POLE/POLD1 mutations and beneficial clinical outcomes to immune checkpoint inhibitor (ICI) therapy This study aims to investigate the genomic characteristics of POLE/POLD-mutant tumors and the prognostic value of POLE/POLD mutation for ICI treatment. METHODS: Genomic data of 21,074 patients with 23 cancer types were retrieved from Burning Rock variant database (BR VarDB). The prevalence and spectra of POLE and POLD1 mutations were assessed and compared with that in The Cancer Genome Atlas (TCGA) samples. The correlations of POLE/POLD1 mutation with tumor mutational burden (TMB) and microsatellite instability (MSI) were investigated. The prognostic value of POLE/POLD1 mutations was also explored in 2,487 ICI-treated patients from published studies. RESULTS: BR VarDB samples displayed a similar mutational prevalence of POLE (3.2% vs. 3.2%) and POLD1 (1.4% vs. 1.6%, P=0.248) versusTCGA samples, but a slightly lower frequency of POLE and POLD1 co-mutations (0.21% vs. 0.43%, P

Purpose: To evaluate the effects of intravitreal anti-VEGF agents in a rabbit model of open-globe injury (OGI).Methods: OGI was induced in the right eyes of 75 Belgian rabbits by making 5 mm circumferential incision placed 6 mm behind the limbus. The rabbits were divided into 4 groups: control (n = 5), OGI group (n = 40), and intravitreal Ranibizumab and Conbercept (n = 15 each). Ranibizumab or Conbercept was injected into the vitreous at 0.5 hours, 3 days, or 7 days. Vitreous fluid was collected, and levels of growth factors and cytokines were measured by enzyme-linked immunosorbent assay (ELISA). On day 28 after OGI, B scan examination and histological examination were performed to evaluate intravitreal proliferation and formation of epiretinal fibrosis.Results: Vitreous levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), and plasminogen activator inhibitor-1 (PAI-1) were significantly increased in rabbit eyes after OGI. Compared to eyes in OGI group, anti-VEGF treatments significantly reduced these growth factors and cytokines. Among the 7 eyes examined from each group for intravitreal proliferative changes, they were found in 7 of 7 (100%) in OGI group and were decreased by Ranibizumab and Conbercept to 5 of 7 (71.4%) and 4 of 7 (57.1%), respectively. Both Ranibizumab and Conbercept inhibited epiretinal scar formation at the wound site, with Conbercept showing the greatest effect (maximal length of scar (L), LOGI = 503 ± 82.44 μm, LRanibizumab = 355 ± 43.66 μm, and LConbercept = 250.33 ± 36.02 μm).Conclusion: Anti-VEGF treatments after OGI significantly attenuated the upregulation of growth factors and cytokines in the vitreous and prevented intravitreal proliferation and epiretinal scar formation and thus may protect against the development of posttraumatic complications such as proliferative vitreoretinopathy (PVR).

Background Profound chemoresistance is a prominent and intractable problem in pancreatic cancer. Gemcitabine, a first-line chemotherapeutic drug for pancreatic cancer, has provided only minimal benefits for patients; however, the underlying mechanisms remain to be investigated. Enhanced aerobic glycolysis has been suggested to be correlated with the phenotype of drug resistance, while MALAT1 has been indicated to be associated with poor gemcitabine response. However, the implicated regulatory mechanisms still need to be further explored. Methods The mRNA level of MALAT1, HIF-1α, and glycolytic enzymes were analyzed by qRT-PCR. The protein level of HIF-1α and glycolytic enzymes were detected by western blot analysis. The glucose uptake and lactate level were measured by glucose uptake and lactate production assay, respectively. The cell apoptosis was evaluated by apoptosis analysis using Annexin V/propidium iodide (PI) staining. The sensitivity to gemcitabine was measured by MTT assay. The binding of HIF-1α to the promoter of MALAT1 was tested by ChIP assay. The xenograft model of pancreatic cancer was established to examine the combined effect of MALAT1 knockdown and gemcitabine chemotherapy in vivo. Results In this study, we showed that low concentrations of gemcitabine promoted the expression of key glycolytic enzymes, such as GLUT1, HK2, and LDHA, as well as glucose uptake and lactate production in pancreatic cancer cells, while inhibition of glycolysis suppressed gemcitabine chemoresistance. In addition, we found that MALAT1 expression was induced by gemcitabine and mediated enhanced glycolysis and chemoresistance. Silencing MALAT1 inhibited the level of gemcitabine-induced HIF-1α expression and reinforced gemcitabine-induced apoptosis in vitro and in vivo. Furthermore, HIF-1α could bind the promoter of MALAT1 transcriptionally and mediate the glycolysis induced by gemcitabine. Conclusions Our data suggest a critical role of glycolytic metabolism in acquired gemcitabine resistance through the positive feedback loop of MALAT1 and the HIF-1α signaling pathway. Our results will provide a basis for developing potential therapeutic targets to reverse gemcitabine resistance.

Liver ischemia-reperfusion (I/R) injury is a pathological process that often occurs during liver and trauma surgery. This study aimed to investigate the protective effect and potential mechanisms of sufentanil on hepatic I/R injury. I/R rat model and hypoxic/reoxygenation (H/R)-induced buffalo rat liver (BRL)-3A cell model were established. Following pretreatment with sufentanil, the enzymatic activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in rat serum and the changes of hepatic histopathology were evaluated to track the extent of liver injury. The levels of inflammatory factors were determined with ELISA kits and RT-qPCR. The infiltration of macrophages was assessed after detecting monocyte chemoattractant protein 1 (MCP-1) and F4/80 expression. Additionally, apoptosis was measured by means of TUNEL staining, and gene expression related to apoptosis was examined using RT-qPCR and western blotting. Then, TP53BP2 was overexpressed in BRL-3A cells exposed to H/R condition to evaluate whether sufentanil defended the liver against injury by regulating TP53BP2 expression. Moreover, the potential binding site of ATF4 on the TP53BP2 promoter was analyzed using JASPAR databases and verified by chromosomal immunoprecipitation (ChIP) assay. Furthermore, TP53BP2 expression and endoplasmic reticulum stress (ERS)-related protein levels were determined after ATF4 was overexpressed in sufentanil-treated BRL-3A cells. Results revealed that sufentanil significantly improved hepatic I/R injury, decreased the levels of inflammatory factors, and alleviated hepatocyte apoptosis. Notably, upregulated TP53BP2 expression was observed in hepatic tissues, and TP53BP2 overexpression markedly reversed the protective effects of sufentanil on the inflammation and apoptosis in H/R-stimulated BRL-3A cells. Additionally, ATF4 was confirmed to combine with the TP53BP2 promoter. ATF4 upregulation attenuated the inhibitory effects of sufentanil on the expression of TP53BP2 and ERS-associated proteins. These findings demonstrated that sufentanil protects the liver from inflammation and apoptosis injury induced by I/R by inhibiting ATF4 expression and further suppressing TP53BP2 expression, suggesting a promising therapeutic candidate for the treatment of liver I/R injury.

To explore the possibility of predicting the clinical types of Corona-Virus-Disease-2019 (COVID-19) pneumonia by analyzing the non-focus area of the lung in the first chest CT image of patients with COVID-19 by using automatic machine learning (Auto-ML). 136 moderate and 83 severe patients were selected from the patients with COVID-19 pneumonia. The clinical and laboratory data were collected for statistical analysis. The texture features of the Non-focus area of the first chest CT of patients with COVID-19 pneumonia were extracted, and then the classification model of the first chest CT of COVID-19 pneumonia was constructed by using these texture features based on the Auto-ML method of radiomics, The area under curve(AUC), true positive rate(TPR), true negative rate (TNR), positive predictive value(PPV) and negative predictive value (NPV) of the operating characteristic curve (ROC) were used to evaluate the accuracy of the first chest CT image classification model in patients with COVID-19 pneumonia. The TPR, TNR, PPV, NPV and AUC of the training cohort and test cohort of the moderate group and the control group, the severe group and the control group, the moderate group and the severe group were all greater than 95% and 0.95 respectively. The non-focus area of the first CT image of COVID-19 pneumonia has obvious difference in different clinical types. The AUTO-ML classification model of Radiomics based on this difference can be used to predict the clinical types of COVID-19 pneumonia.

BackgroundPrevious studies have indicated coronavirus disease 2019 (COVID-19) patients with cancer have a high fatality rate.MethodsWe conducted a systematic review of studies that reported fatalities in COVID-19 patients with cancer. A comprehensive meta-analysis that assessed the overall case fatality rate and associated risk factors was performed. Using individual patient data, univariate and multivariable logistic regression analyses were used to estimate odds ratios (OR) for each variable with outcomes.ResultsWe included 15 studies with 3019 patients, of which 1628 were men; 41.0% were from the United Kingdom and Europe, followed by the United States and Canada (35.7%), and Asia (China, 23.3%). The overall case fatality rate of COVID-19 patients with cancer measured 22.4% (95% confidence interval [CI] = 17.3% to 28.0%). Univariate analysis revealed age (OR = 3.57, 95% CI = 1.80 to 7.06), male sex (OR = 2.10, 95% CI = 1.07 to 4.13), and comorbidity (OR = 2.00, 95% CI = 1.04 to 3.85) were associated with increased risk of severe events (defined as the individuals being admitted to the intensive care unit, or requiring invasive ventilation, or death). In multivariable analysis, only age greater than 65 years (OR = 3.16, 95% CI = 1.45 to 6.88) and being male (OR = 2.29, 95% CI = 1.07 to 4.87) were associated with increased risk of severe events.ConclusionsOur analysis demonstrated that COVID-19 patients with cancer have a higher fatality rate compared with that of COVID-19 patients without cancer. Age and sex appear to be risk factors associated with a poorer prognosis.

BackgroundEarly onset colorectal cancer (EO CRC) is a heterogeneous colorectal cancer subtype with obvious hereditary tendencies and increasing incidence. We sought to determine the susceptibility genes and molecular characteristics of EO CRC.Methods330 EO metastatic CRC (mCRC) (≤55 years) and 110 average-onset (AO) mCRC patients (>55 years) were enrolled. Capture-based targeted sequencing was performed on tumor tissue and paired white blood cells using a sequencing panel of 520 genes. The association between molecular alterations and overall survival (OS) was analyzed.ResultsOf the 330 EO mCRC patients, 31 carried pathogenic or likely pathogenic germline mutations, with 16 of them diagnosed with lynch syndrome. Fifteen patients had germline mutations in non-mismatch repair genes, including four in MUTHY, three in RAD50, one in TP53, and eight in other genes. Twenty-nine genes were recurrently mutated in EO mCRC, including TP53, APC, KRAS, SMAD4, and BRCA2. The majority of genomic alterations were comparable between EO and AO mCRC. EO mCRC patients were more likely to have a high tumor mutation burden (p < 0.05). RNF43, RBM10, TSC, and BRAF V600E mutations were more commonly observed in EO mCRC, while APC, ASXL1, DNMT3B, and MET genes were more commonly altered in AO patients. At the pathway level, the WNT pathway was the only differentially mutated pathway between EO and AO mCRC (p < 0.0001). The wild-type WNT pathway (p = 0.0017) and mutated TGF-β pathway (p = 0.023) were associated with unfavorable OS in EO mCRC.ConclusionsApproximately one in 10 EO mCRC was associated with hereditary tumors. The spectrum of somatic alterations was largely comparable between EO and AO mCRC with several notable differences.

Background Recent studies on the favorable prognosis of ground-glass opacities (GGO) featured lung adenocarcinoma compared with solid nodules were limited to small tumors measuring ≤3.0 cm. This study aimed to investigate whether GGO component could predict better prognosis in patients with large subsolid lesions exceeding 3cm compared with small solid nodules within the same clinical T category. Methods From 2010 to 2015, a total of 1010 patients with completely resected clinical N0 lung adenocarcinoma were enrolled, including 860 solid lesions and 150 subsolid lesions exceeding 3cm. To analyze the prognostic significance of GGO component, propensity score matching adjusting solid component size was performed. Results After propensity score matching, 144 pairs of patients were finally analyzed. The mean size of the solid component was 23.7mm in the GGO group and 24.4mm in the solid group(p=0.450). The GGO group had significantly better overall survival and recurrence-free survival (p=0.011 and p=0.003, respectively), which were also validated in patients with solid-predominant lesions. Subgroup analysis showed the GGO group was associated with better prognosis in each clinical T category. Conclusions The prognosis of patients with GGO lesions exceeding 3cm was better than that of patients with small solid lesions even within the same clinical T category. Clinical T classification incorporating GGO component may provide better prognostic prediction for patients with lung cancer exceeding 3cm.

In 2020, the new type of coronal pneumonitis became a pandemic in the world, and has firstly been reported in Wuhan, China. Chest CT is a vital component in the diagnostic algorithm for patients with suspected or confirmed COVID-19 infection. Therefore, it is necessary to conduct automatic and accurate detection of COVID-19 by chest CT.The clinical classification of patients with COVID-19 pneumonia was predicted by Radiomics using chest CT.From the COVID-19 cases in our institution, 136 moderate patients and 83 severe patients were screened, and their clinical and laboratory data on admission were collected for statistical analysis. Initial CT Radiomics were modeled by automatic machine learning, and diagnostic performance was evaluated according to AUC, TPR, TNR, PPV and NPV of the subjects. At the same time, the initial CT main features of the two groups were analyzed semi-quantitatively, and the results were statistically analyzed.There was a statistical difference in age between the moderate group and the severe group. The model cohort showed TPR 96.9%, TNR 99.1%, PPV98.4%, NPV98.2%, and AUC 0.98. The test cohort showed TPR 94.4%, TNR100%, PPV100%, NPV96.2%, and AUC 0.97. There was statistical difference between the two groups with grade 1 score (P = .001), the AUC of grade 1 score, grade 2 score, grade 3 score and CT score were 0.619, 0.519, 0.478 and 0.548, respectively.Radiomics' Auto ML model was built by CT image of initial COVID -19 pneumonia, and it proved to be effectively used to predict the clinical classification of COVID-19 pneumonia. CT features have limited ability to predict the clinical typing of Covid-19 pneumonia.